Beta-Amyloid (Aβ) peptides are thought to be a causative agent for Alzheimer's disease (“AD”) through the formation of insoluble Aβ peptide fibrils and deposition of these fibrils to form amyloid plaques. The formation of such plaques within the area of the brain critical for memory and other cognitive functions is thought to lead to dementia associated with this disease (see Selkoe, 1994, J. Neuropathol. Exp. Neurol. 53:438-447). Beta-Amyloid peptides comprise a group of peptides 39-43 amino acids long that are proteolytically processed from amyloid precursor protein (APP), by both β-secretase and γ-secretase at the amino- and carboxyl-terminus, respectively. There are at least five distinct isoforms of APP: 563, 695, 714, 751, and 770 amino acids in length, respectively (see Wirak et al., 1991 Science 253:323). These isoforms of APP are generated by alternative splicing of primary transcripts of the APP gene. Numerous missense mutations have been identified in APP in families with autosomal dominant early-onset Alzheimer's disease. Some mutations cluster near the secretase cleavage sites and affect APP metabolism either by increasing the production or the proportion of Aβ forms (e.g., Aβ42), which tends to be more fibrillogenic and to aggregate faster than other forms. Neuronal toxicity may reside in the large molecular weight fibrils which are formed via aggregation of soluble Aβ peptides into insoluble fibrils and, subsequently, fibril incorporation into amyloid plaques. An intermediate fibril form is the protofibril (PF) form, a large molecular weight oligomeric form of Aβ peptides which is soluble in vitro and may be isolated as an approximately ˜670 kDa entity. Thus, the in vitro formation of insoluble Aβ peptide fibrils is the end result of the initial oligomerization of Aβ peptide to form a structurally distinct, soluble higher molecular weight protofibril form. These transient protofibrils structures are precursor to the amyloid fibers responsible for cell dysfunction and neuronal loss in Alzheimer's disease (AD) and other protein aggregation diseases.
Various treatments have been forwarded in attempts to prevent the formation of Aβ peptide, for example, inhibitors to prevent the proteolytic processing of APP. Also, immunotherapy strategies such as administration of anti-Aβ antibodies (to induce clearance of amyloid deposits) or immunization with Aβ peptide antigens (to promote a humoral response) have been enlisted in an attempt to reduce plaque size and density.
U.S. Pat. No. 7,179,463, issued to Lannfelt et al., discloses a method of treating Alzheimer's disease by administering an antibody raised against a protofibril consisting of the Arctic mutation within the Aβ peptide coding region. No exemplification of raised antibodies are presented in the specification and no comparison as to affinity for low molecular weight forms of Aβ peptide are presented.
U.S. Pat. Nos. 6,761,888 and 6,750,324, issued to Schenk et al., disclose a series of antibodies which recognize various epitopes along the amino acid sequence of Aβ42. Antibodies specific for the N-terminus and mid-regions of Aβ42 showed efficacy in reducing plaque both ex vivo and in vivo.
Despite current knowledge in the field of treating and preventing Alzheimer's disease, there remains a need for an improved compositions and methods of treating and/or preventing this disease. The compositions and methods of the present invention address and meet these needs by disclosing antibodies specific for protofibrillar forms of Aβ peptide while showing minimal detectable affinity against low molecular weight forms of the Aβ peptide. Pharmaceutically effective compositions comprising such an antibody or antibodies will be useful in treating and/or preventing beta-amyloid plaque deposition known to be associated with the onset and progression of Alzheimer's disease.